1. Field of the Invention
The present invention relates to controlled-release organic nitrate formulations for oral administration. More particularly, the present invention is directed to nonpareils or sugar spheres coated with an organic nitrate triturate mixed with or without a carrier, a seal coat, and a polymeric membrane as means for controlling the diffusion and release of the organic nitrate. The present invention is also directed to administering the formulation to patients once per day so as to delay or prevent the onset of chest pain for at least sixteen hours after the dose without inducing pharmacologic tolerance to the drug.
2. Discussion of Background and Material Information
Organic nitrates have been used for over a century by physicians for the treatment of cardiovascular disease. Organic nitrates function as relaxants of smooth muscle and especially as dilators of blood vessels. As such, they are used in the treatment of angina pectoris, in which dilation of the coronary vasculature improves myocardial blood flow and oxygen delivery. A second mechanism of action in angina is the reduction of peripheral resistance due to relaxation of veins and arterioles, reducing cardiac workload and, therefore, myocardial oxygen demand. In the treatment of congestive heart failure, dilation of the pulmonary vasculature results in increased blood return to the heart and decreased cardiac preload and afterload, leading to improved cardiac output.
Nitroglycerin, which has been the traditional mainstay in the acute treatment of angina, is well-absorbed from the gastrointestinal tract, but has an extremely short plasma half-life due to extensive first-pass metabolism. These pharmacokinetics have led to the use of nitroglycerin as a short-acting nitrate. In this sense, and because of its low vapor pressure, nitroglycerin is often used sublingually to reverse attacks of acute angina.
Development of a controlled-release, long-acting nitroglycerin formulation, however, has been impeded mainly because of the pharmacokinetics and low vapor pressure of nitroglycerin. For example, attempts to solve these problems with oral or transdermal patch preparations has led to formulations which extend delivery of active drug for up to twenty four hours. A serious disadvantage associated with conventional extended delivery formulations, however, is that continually elevated levels of serum nitrates induce tolerance and reduced drug efficacy within a relatively short time.
The present invention, therefore, is directed to a controlled-release formulation which can be administered orally, once per day, causing therapeutic serum levels for about eighteen hours, thus effectively achieving anginal prophylaxis without induction of tolerance.